Interpregnancy interval and adverse perinatal outcomes: A within‐individual comparative method

Abstract Background and Aim Previously observed associations between interpregnancy interval (IPI) and perinatal outcomes using a between‐individual method may be confounded by unmeasured maternal factors. This study aims to examine the association between IPI and adverse perinatal outcomes using within‐individual comparative analyses. Methods We studied 10,647 individuals from the National Institute of Child Health and Human Development Consecutive Pregnancies Study in Utah with ≥3 liveborn singleton pregnancies. We matched two IPIs per individual and used conditional logistic regression to examine the association between IPI and adverse perinatal outcomes, including preterm birth (PTB, <37 weeks’ gestation), small‐for‐gestational‐age (SGA, <10th percentile of sex‐specific birthweight for gestational age), low birthweight (LBW, <2,500 g), and neonatal intensive care unit (NICU) admission. Point and 95% confidence interval (CI) estimates were adjusted for factors that vary across pregnancies within individuals. Results CIs did not unequivocally support either an increase or a decrease in the odds of PTB (adjusted odds ratio [aOR]: 1.31, 95% CI: 0.87, 1.96), SGA (aOR: 0.81, 95% CI: 0.51, 1.28), LBW (aOR: 1.59, 95% CI: 0.90, 2.80), or NICU admission (aOR: 0.96, 95% CI: 0.66, 1.40) for an IPI <6 months compared to 18–23‐months IPI (reference), and neither did the CIs for the aOR of IPIs of 6–11 and 12–18 months compared to the reference. In contrast, an IPI ≥24 months was associated with increased odds of LBW (aOR: 1.66, 95% CI: 1.03, 2.66 for 24–29 months; aOR: 2.27, 95% CI: 1.21, 4.29 for 30–35 months; and aOR: 2.09, 95% CI: 1.17, 3.72 for ≥36 months). Conclusions Using a within‐individual comparative method, we did not find evidence that a short IPI compared to the recommended IPI of 18–23 months was associated with increased odds of PTB, SGA, LBW, and NICU admission. IPI ≥ 24 months was associated with increased odds of delivering an LBW infant.


| INTRODUCTION
5][6] The dose-response relationship between the adverse perinatal outcomes and IPI is frequently described in the literature as J-shaped, that is, the proportion of adverse outcomes is higher for IPI < 6 and ≥60 months but is lower for the interval between 18 and 23 months. 5,7According to the World Health Organization, an optimal IPI of at least 24 months is recommended after a live birth given the lowest risk of adverse perinatal outcomes. 8is recommendation was based on studies mostly from low-and middle-income countries, and thus its relevance to individuals from high-income countries such as the United States remains unclear. 6st studies examining the association between IPI and perinatal outcomes have used a between-individual comparative method, where the perinatal outcomes of the individuals with either short or long IPIs were compared to the outcomes of other individuals with the recommended IPI.The reported positive associations of short and long IPIs with adverse perinatal outcomes, however, might be attributed to unobserved confounding. 9,10To overcome potential confounding issues, recent studies examined the relationship between IPI and adverse perinatal outcomes using a within-individual comparative method, whereby each study participant serves as their own control.That is, the contrast between two perinatal outcomes, one observed after a nonoptimal interval and one after the optimal or recommended IPI, is carried out for the same pregnant individual who provides data for at least two intervals (e.g., three successive deliveries).In those studies, the estimates obtained from the withinindividual comparative method were mostly attenuated as compared to those based on the between-individual method, [11][12][13][14] thus supporting the speculation that previously observed associations between IPI and perinatal outcomes might be partly explained by individual heterogeneity. 15though the within-individual comparative method has recently been utilized in IPI research, such studies are relatively limited in the United States. 14Most existing within-individual studies in this area often lack information on key time-varying confounders, including socioeconomic factors, prepregnancy body mass index (BMI), smoking during pregnancy, and maternal co-morbidities.
Experts in the field have highlighted the need to adjust for confounders that vary between individual's pregnancies.They also emphasize the importance of assessing the generalizability of the cohort used in the within-individual analysis and exploring the potential influence of the outcomes of the previous birth and pregnancy losses on the IPI and perinatal outcomes relationship by conducting additional sensitivity analysis. 16ven the limited studies conducted in the United States using a within-individual comparative method, 14 the limitations of the existing studies and the recent recommendations on good practices in IPI studies, 16 we aimed to examine the association between IPI and PTB, SGA, LBW, and neonatal intensive care unit (NICU) admission in the subsequent pregnancy using a within-individual comparative method in a cohort of US individuals from the state of Utah.

| Data source
We conducted a retrospective matched cohort study to examine the association between IPI and adverse perinatal outcomes among individuals from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Consecutive Pregnancies Study. 17

Key points
What is already known • Short and long interpregnancy intervals (IPIs) were associated with increased odds of adverse perinatal outcomes using a between-individual method.

What this study adds
• The within-individual comparative method showed that a short compared to recommended IPI was not associated with increased odds of small-for-gestational-age, preterm birth, low birthweight (LBW), and neonatal intensive care unit admission.IPI ≥ 24 months was associated with increased odds of delivering an LBW newborn.

Clinical implications
• Previously observed associations between IPI and adverse perinatal outcomes using a between-individual method may be due to unmeasured confounding.Intervening on a short IPI itself may not be beneficial for decreasing the prevalence of adverse perinatal outcomes.
discharge summaries were linked to each delivery.All participating institutions obtained approval for the study and a waiver of informed consent from their individual institutional review boards.

| Study population
Of the total of 51,086 individuals enrolled in the NICHD Consecutive Pregnancies Study, we excluded individuals with only two births during the study period as these would have contributed to only one IPI.We also excluded individuals with multiple gestations or stillbirths for any of the first three pregnancies during the study period (Figure 1).Multiple gestations were excluded due to their unique physiological impact and higher nutritional demands compared to singleton pregnancies, the potential for confounding due to factors such as assisted reproductive technologies and secondary infertility, and the limited sample size available for stratified analysis.We excluded stillbirths to minimize potential confounding, as individuals experiencing stillbirth often have shorter IPIs and underlying conditions that can affect subsequent pregnancies. 18The final analytical sample included 10,647 individuals with ≥3 liveborn singleton deliveries during the study period.

| Exposure
The exposure, IPI, was defined as the time interval between the previous live birth and the estimated conception date of the subsequent pregnancy, which was calculated as the last menstrual period for the subsequent pregnancy minus the date of the previous delivery.IPI was grouped into seven categories: 0-5, 6-11, 12-17, 18-23 (reference), 24-29, 30-35, and ≥36 months.For each study participant, there were two IPIs: interval between the first delivery and the second pregnancy's conception date and the second interval between the second delivery and the third pregnancy's conception date.If a study participant had more than three deliveries (i.e., more than two IPIs) during the study period, only the first three deliveries (and first two IPIs) were examined.

| Outcomes
We studied four binary perinatal outcomes: PTB (delivery at <37 completed weeks of gestation), SGA (<10th percentile of national birthweight centiles for sex and gestational age), 19 LBW (birthweight <2,500 g), and NICU admission.Gestational age was based on the best obstetric estimate obtained from electronic medical records.

| Covariates
In our study's method, each pregnant individual represents a separate stratum, thus individual-specific factors (measured and unmeasured) that are shared between pregnancies can be controlled for by appropriate regression modeling. 20The model, however, needs to also adjust for factors that change across an individual's pregnancies.Thus, we adjusted for the variables that can potentially change between pregnancies within the same individual, including maternal age at the time of each delivery, insurance type, marital status, smoking during pregnancy, prepregnancy BMI, parity, mode of delivery, and maternal co-morbidity status.Maternal co-morbidity status included the presence of at least one of the following: heart disease, chronic hypertension, diabetes mellitus, thyroid disorder, asthma, and renal disease.Maternal chronic conditions were ascertained from medical records and supplemented with ICD-9 codes.These potential confounders were selected based on previous literature 5,16,21,22 and availability.

| Statistical analysis
Conditional logistic regression was used to perform within-individual comparisons. 23In this regression, only individuals with discordant outcomes contribute to the overall estimate of the effect. 20The unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CI) for the association between IPI and each of the adverse perinatal outcomes were estimated.All analyses were performed using SAS ® 9.4 software.

| Missing data
We performed a complete case analysis.Since the proportions of missing data for incomplete variables were small (ranging from 0.019% for marital status to 2.7% for prepregnancy BMI), the application of missing data methods (e.g., imputation) was not deemed necessary.

| Sensitivity analyses
We performed sensitivity analyses to examine the robustness of the estimates with respect to three different data selection criteria.(1)   Scenario A: we restricted our sample to only individuals with consecutive first, second, and third deliveries (n = 8,361) during the study period, given the possible influence of pregnancy losses on the association between IPI and outcomes. 16We examined whether deliveries were consecutive by checking if gravidity increased more than parity, indicating that a study participant had a pregnancy loss before 20 weeks of gestation.( 2

| Supplementary analyses
We performed several supplementary analyses to explore the association between IPI and outcomes in more depth.(1) Given that individuals with ≥3 births may be different from individuals with only 2 births, we assessed the generalizability of our findings by comparing the characteristics and perinatal outcomes of these two groups of individuals.We also performed between-individual comparisons (unconditional logistic regression) for the sample of individuals with only two births and estimated the adjusted ORs (aORs) and 95% CIs for the association between IPI and adverse outcomes.(2) We used post-birth intervals 9,13 in a negative controls 24 analysis to detect the potential influence of unmeasured confounding on the association between post-birth IPI (IPI between second and third birth) and odds of perinatal outcomes of the second birth for our sample of individuals with ≥3 births.The goal was not to investigate a causal relationship since, due to the chronological sequence of the events, the post-birth interval cannot have an effect on the outcome of the second birth.Rather, the presence of an association may reflect the impact of factors that are common to both adverse perinatal outcomes and the length of the IPI.

| RESULTS
The final analytical sample consisted of 10,647 individuals, which accounted for 21,294 IPI observations (two per study participant).At the second birth, around 58% of individuals conceived after IPIs of <18 months (6.7% after IPI <6 months), and around 20% conceived after IPIs ≥24 months.At the third birth, around 47% of individuals conceived after IPIs <18 months (4.7% after IPI < 6 months), and around 31% of deliveries occurred after IPIs ≥24 months.Only about 22% of individuals conceived after the recommended IPI of 18-23 months after their first and second deliveries.Most individuals were white (89%), under 25 years, married (89%), with private insurance (75%), and with normal prepregnancy BMI (63%) at the study entry (Table 1).
The unadjusted proportions of the perinatal outcomes during the second and third births are presented in Figure 2. The observed proportions of adverse perinatal outcomes in the sample were low.The distribution of these outcomes varied across different IPI categories, with a tendency for increased proportions in the shorter and longer IPI categories, compared to the recommended IPI of 18-23 months.The pattern of adverse outcomes by IPI categories was consistent for second and third births (Figure 2).

| IPI and odds of adverse perinatal outcomes (within-individual comparison)
The analysis did not demonstrate increased or decreased odds for any of the four perinatal outcomes associated with IPI intervals for interval ≥36 months.

| Sensitivity analyses
The results of the sensitivity analyses restricted to individuals with three consecutive births during the study period (Scenario A), further  Table S1).In Scenarios B and C, the adjusted estimates of the ORs for LBW were still greater than 1 at longer IPIs, although the associated larger uncertainty meant that most of the p values were greater than 0.05.

| Between-individual comparison
The supplementary analysis showed that individuals with only two births compared to those with ≥3 births on average waited longer after the first birth to conceive (mean IPI 22.4 vs. 17.1 months), were older at the second birth (mean age 28.4 vs. 26.8),were more likely to be obese or overweight at the beginning of their second pregnancy (41% vs. 36%), and more likely had comorbidities (18% vs. 15%) (Supporting Information S1: Table S2).The proportions of the adverse perinatal outcomes for individuals with only two births and ≥3 births were similar in both groups: higher rates of outcomes at short and long IPI intervals and lowest at the recommended IPI of  S3).
In contrast, post-birth intervals longer than 24 months were not associated with increased odds of any of the outcomes in the previous pregnancy (Supporting Information S1: Table S4).

| Strengths of the study
The within-individual comparative method controls for all the characteristics that remain the same within the individual.In addition, detailed information available in our dataset for each delivery of the  For unadjusted of the 10,647 pairs, 1,001 were informative for PTB, 881 for SGA, 552 for LBW, and 1,262 for NICU admission.
For adjusted models, 948 pairs were informative for PTB, 850 for SGA, 527 for LBW, and 1,222 for NICU admission (due to missing values for the covariates).
Abbreviations: CI, confidence interval; IPI, interpregnancy interval; LBW, low birth weight; NICU, neonatal intensive care unit; OR, odds ratio; PTB, preterm birth; SGA, small-for-gestational-age. a Adjusted model accounted for characteristics that varied or could potentially vary between pregnancies within the same individual: individual's age, marital status, health insurance, prepregnancy BMI, chronic conditions, smoking during pregnancy, parity, mode of delivery; pregnancy order included in the adjusted model to allow for different intercepts at the second and third births.
Individual's chronic conditions include having at least one of heart disease, chronic hypertension, diabetes mellitus, thyroid disorder, asthma, and renal disease.
comparative method studies, 16 we performed several sensitivity and perinatal outcomes indicates that confounding may be less of an issue for the long IPI.Our post-birth interval analysis results were similar to the results from other studies. 9,13mpared to consistently demonstrated associations in previous research that used between-individual comparisons, our study does not support a relationship between short IPI and adverse perinatal outcomes. 5,6Our results of no evidence of increased odds of adverse perinatal outcomes after short IPI are mostly consistent with the previous research using within-individual comparison.The observed unfavorable association between longer intervals and LBW in our study might be explained by the "women's physiological regression" hypothesis proposed by Zhu et al. 7 The hypothesis states that due to a long IPI between pregnancies (and individual aging), an individual's natural reproductive capacity gradually declines and becomes similar to a nulliparous individual.A systematic review, however, did not find evidence to support the "women's physiological regression" hypothesis as a biological mechanism explaining the effect of long IPIs on adverse perinatal outcomes. 27creased odds of LBW after long IPI observed in our study may be a marker of biological or social mechanisms that lead individuals to have long IPI and also result in delivering an LBW infant.Conditions, such as subfertility and secondary infertility can contribute to a longer IPI.Studies suggest that subfertility and secondary infertility are associated with an increased risk of perinatal outcomes, irrespective of fertility treatment. 28Furthermore, individuals who undergo assisted reproductive technology treatments usually are older and have a higher risk of adverse pregnancy outcomes compared to those who conceive naturally. 29Not accounting for all the factors that change across pregnancies within the same individual may be the reason for the observed association between long IPI and increased odds of LBW.

| CONCLUSION
Using a within-individual comparison method, we did not find evi- LBW infant in the subsequent pregnancy.The previously observed consistent association between short IPI categories and perinatal outcomes may be due to residual confounding rather than the length of the IPI.Intervening on short IPI may not be beneficial for decreasing the rates of adverse perinatal outcomes.
Data on consecutive pregnancies were collected from 51,086 individuals delivering at ≥20 weeks of gestation in 20 hospitals in the state of Utah during the period of 2002-2010.During the study period, around 78.2% (n = 39,974) of the individuals had only two deliveries and 21.8% of individuals (n = 11,112) contributed three or more deliveries.Detailed information on maternal demographics, past medical history, reproductive and perinatal history, pregnancy, labor and delivery outcomes, postpartum, and newborns was extracted from electronic medical records and in-patient hospital discharge summaries. 17Codes from the International Classification of Diseases, ninth revision (ICD-9) from maternal and newborn ) Scenario B: we further restricted the Scenario A sample to individuals who were nulliparous at the beginning of the study (n = 4,889).(3) Scenario C: we further restricted the Scenario B sample to individuals without corresponding adverse perinatal outcomes in the first delivery (Figure 1).

18- 23
months.The adjusted results of the between-individual comparisons (traditional logistic regression) for the sample of individuals with only two births showed that short IPI categories were associated with increased odds of PTB, LBW, and NICU admission.Longer IPIs were associated with increased odds of SGA, LBW, and NICU admission (Supporting Information S1: Table

4 | DISCUSSION 4 . 1 |
Principal findingsWe used a within-individual comparative method design to examine the association between IPI and odds of PTB, LBW, SGA, and NICU admission in a sample of 10,647 individuals with ≥3 liveborn singleton deliveries from the state of Utah.Using a within-individual comparative method, we did not find evidence that short IPI F I G U R E 2 Proportion of adverse perinatal outcomes for second and third births by interpregnancy interval in individuals with ≥3 liveborn singleton pregnancies (n = 10,647), National Institute of Child Health and Human Development (NICHD) consecutive pregnancies study, Utah, 2002-2010.IPI, interpregnancy interval; LBW, low birthweight; NICU, neonatal intensive care unit; SGA, small-for-gestational-age. categories compared to the recommended IPI of 18-23 months were associated with increased odds of SGA, PTB, LBW, and NICU admission.However, longer IPIs compared to the reference IPI were associated with increased odds of delivering an LBW infant in the subsequent pregnancy.These results were similar in the sensitivity analyses.Consistent with previous studies, traditional between-individual comparative analyses for the sample of individuals with only two births demonstrated evidence of increased odds of adverse outcomes with both short and long IPI categories.We identified some differences in the characteristics of individuals with only 2 versus ≥3 births during the study period.This study showed that different methodologies (within-individual and between-individual comparisons) produce different results and may lead to different conclusions.
same individual provided the opportunity to further adjust for a range of factors that can potentially change across different pregnancies within the same study participant.Compared to other studies that utilized a within-individual comparative method, we adjusted for several time-varying characteristics (marital status, smoking during pregnancy, insurance type, maternal chronic co-morbidities, prepregnancy BMI) that may change across second and third pregnancies within the same individual.To overcome the common methodological issues with the birth spacing studies10 and following experts' recommendations on good practices for within-individual T A B L E 2 ORs and 95% CI for the association between interpregnancy interval and adverse perinatal outcomes in individuals with at least three liveborn singleton births (n = 10,647), NICHD consecutive pregnancies study,Utah, 2002-2010.

4 . 3 |
supplementary analyses, including (a) an analysis to evaluate the potential influence of the pregnancy losses and outcome of the previous birth on IPI and perinatal outcomes relationship; (b) an analysis to assess the generalizability of the cohort used in the within-individual analysis by comparing the results and characteristics of the cohorts of individuals with only 2 and ≥3 births; and (c) an analysis to adjust for the range of variables that vary between pregnancies, such as marital status, insurance type, smoking during pregnancy, pre-pregnancy BMI, maternal comorbidities.Limitations of the study Most of our study population was White individuals, which represents a significant limitation in terms of racial diversity.Limited racial diversity may potentially impact the generalizability of our findings to more diverse and heterogeneous populations.Additionally, our study population consisted of low-risk individuals, mostly composed of married individuals with private insurance, resulting in relatively low rates of adverse outcomes.Our estimates of the relationships of IPI with adverse outcomes may differ in other populations that are at high risk of adverse outcomes.Due to the study design, only individuals with ≥3 deliveries are included in our study population; as observed in our analysis, these individuals can be different from individuals with fewer deliveries.4.4 | InterpretationOur study supports the recent findings that individual heterogeneity may be an explanation for the frequently observed associations between short IPI and adverse outcomes using a between-individual comparison method.Traditional between-individual comparisons for a sample of individuals with only two births demonstrated an increased risk associated with short and long IPI and adverse perinatal outcomes, which can indicate the inappropriate adjustment for confounders or presence of unmeasured confounders in betweenindividual comparison studies.The post-birth interval analysis results also demonstrated evidence of possible confounding by maternal factors.A strong positive association between short post-birth interval and the risk of prior adverse perinatal outcomes may indicate confounding between short IPI and adverse outcomes.The absence of association between long post-birth intervals and prior dence that short IPIs compared to the reference IPI of 18-23 months were associated with increased odds of SGA, LBW, PTB, and NICU admission.Longer IPIs compared to the reference IPI of 18-23 months were associated with increased odds of delivering an SEVOYAN ET AL. | 9 of 11 Maternal and newborn characteristics of the sample (n = 10,647), NICHD consecutive pregnancies study, Utah, 2002-2010.
estimates do not indicate a definite increase or decrease in risk.Intervals longer than 24 months were not associated with higher or lower odds of PTB or NICU admission.The highest OR of 1.04 (95% CI: 0.73, 1.48) for PTB and OR of 1.13 (95% CI: 0.77, 1.65) for NICU admission were observed for IPI 24-29 and ≥36 months, respectively.Since these CIs include 1, however, these results do not definitely indicate an increase or decrease in odds for these out- 26,12As for the long IPIs, in a study of 38,000 individuals from Canada, Hanley et al. found that IPIs ≥60 months were associated with increased odds of LBW (aOR: 1.31, 95% CI: 1.02, 1.68) and NICU admission (aOR: 1.39, 95% CI: 1.02, 1.90).12Classetal studymonstrated that IPI ≥ 60 months was associated with increased odds of SGA (aOR: 1.24, 95% CI: 1.10, 1.40), LBW (aOR: months.11Inastudywithmorethanfive million individuals from Australia, Finland, Norway, and California, Tessema et al. consistently found increased odds of PTB and SGA following IPI categories ≥24 months.25Despiteusingawithin-individualcomparisonmethod in a study with >300,000 individuals from California, however, Shachar et al. found a 20% increase in odds of PTB (95% CI:1.13, 1.27) after IPI < 6 months compared to IPI of 18-23 months and no associations with long IPI.14A Matched analysis in a study from China showed increased odds of PTB, LBW, and SGA after short IPIs and increased odds of PTB and LBW after IPI ≥ 36 months.26